Biguanide Thiazolidinedione

Dr. Sanooz Raheem

Objectives • List examples, mechanism of action, adverse effects and clinical uses

of biguanides• List examples, mechanism of action, adverse effects and clinical uses

of thiazolidinediones• Describe the uses and effects of acarbose as an oral hypoglycemic• List clinical uses of glucagon

Biguanide • Phenformin and metformin introduced in 1950s• Phenformin had high risk of lactic acidosis and withdrawn

Metformin • Little or no hypoglycaemic effect in non diabetics • Hypoglycaemia in diabetics is very rare • Does not stimulate pancreatic beta cells• Improve lipid profile in diabetics

MOA• Does not cause insulin release • Presence of insulin essential for action • Actions are mediated through activation of AMP-dependant protein

kinase

Key features in MOA 1. Mainly suppress gluconeogenesis and glucose output from liver 2. Enhances insulin mediated glucose uptake and disposal in skeletal

muscle and fatinsulin resistance is overcome - glycogen storage in skeletal muscle- reduced lipogenesis in adipose tissue and enhanced fatty acid

oxidation 3. Interferes mitochondrial respiratory chain and promotes peripheral

glucose utilization by anaerobic glycolysis * Metformin retards intestinal absorption of glucose, amino acids and

Vit B12

PK• T ½ - 1.5 to 3 hours • Duration of action 6-8 hours• Cleared by kidneys • Clearance of metformin approximates GFR• Accumulates in renal failure and increases the risk of lactic acidosis

Adverse effects• No serious side effects • Abdominal pain• Anorexia• Bloating• Nausea• Metallic taste • Mild diarrhea • Tiredness • Does not cause hypoglycaemia except very high doses• Lactic acidosis- rare, alcohol ingestion can precipitate • Vit B12 def rarely

Contraindications • Hypotension • Heart failure• Severe hepatic, respiratory and renal disease • Alcoholics • Ketoacidosis • Use of GA

Interactions • Cimetidine and furosemide compete with metformin excretion and

enhance its toxicity

Uses • First choice drug in all T2 DM except not tolerated/ contraindicated• Advantages: - Nonhypoglycaemic - Weight loss promoting- Prevent micro and macro vascular DM complications - No acceleration/ failure of beta cells in T2 DM- Equivalent anti hyperglycaemic efficacy to other drugs - Can be combined with other hypoglycaemic drug* Improve ovulation and fertility in PCOS

Dose DM:Initially 500 mg at morning after 1 wkThen 500mg bd after 1 wk Then 500mg tds Usual max dose 2g but upto 3g used

Modified release:Initially 500mg once daily Increased every 10-15 days Max 2g once daily with evening mealIf no control achieved 1g twice daily

Pioglitazone• Only one thiazolidinedione available• Rosiglitazone withdrawn due to increased risk of MI,CHF, stroke and

death

MOA• Selective agonist for nuclear peroxisome proliferator- activated receptor

gamma • Mainly expressed in fat cells, also in muscle and other cells • Enhances transcription of several insulin responsive genes• Tend to reverse insulin resistance by enhancing GLUT4 expression and

translocation • Glucose entry into muscle and fat improved hepatic gluconeogenesis

suppressed • Activation of genes regulating fatty acid metabolism and lipogenesis in

adipose tissue contributes to insulin sensitizing action • Reduction in lipolysis and plasma fatty acid level • Increased turnover and differentiation of adipose tissue

• Degree of blood sugar reduction is less than SU and metformin • Lowers TG, raises HDL, no significant change in LDL• Due to induced expression of reverse cholesterol transporter and

some apoproteins

PK• Well tolerated • T ½ : 3-5 hours • Duration of action – 24 hours • Metabolized in liver • Interact with OCP and contraceptive failure occurs • Keatconazole inhibits and rifampicin induces metabolism

AR• Plasma volume expansion• Edema• Weight gain• Headache• Myalgia• Mild anaemia • Monotherapy not associated with hypoglycaemia• Rarely hepatic dysfunction • CHF worsened or precipitated • Increases the risk of fracture in elderly CI- liver disease, CHF

Indications • Type 2 DM- Reduce blood glucose and HbA1C- Do not increase insulin - Do not work in low insulin base line - Stooped if <0.5% reduction in HbA1C in 6 months • Supplement SU/Metformin and in case of insulin resistance • Monotherapy in mild cases • When used with insulin- greater fluid retention, weight gain, precipitation

of CHF• Should not be used during pregnancy

Dose :15- 30 mg initially once daily Increased upto 45mg

Alpha glucosidase inhibitors Acarbose •Complex oligosaccharide •Reversibly inhibits alpha glucosidase ( final enzyme for digestion in the brush border of small intestine mucosa)MOA-Slows down and decreases digestion and absorption of polysaccharides and sucrose - Increases GLP-1 release -Postprandial glycaemia is reduced -Regular use lowers HbA1C modestly , change in body weight and lipid level minimal -In diabetics reduces CVS events

Uses :•Mild antihyperglycaemic and a hypoglycaemic •Used as adjuvant with diet/ SU/ metformin in obese

PK: Only a small fraction of the dose absorbed AR: Flatulence, abdominal discomfort, loose stools Patient’s acceptability is poor due to GIT side effects ++ other alpha glucosidase inhibitors: Ex: Miglitol, Voglibose

Contra indications-IBD, predisposition to partial intestinal obstruction, hernia and previous abdominal surgery

Dose: Initially 50mg daily Then 50mg tds After 6-8 weeks 100mg tds Max 200 mg tds

Advice: Chew with mouthful of food or swallow whole with little fluid immediately before food

Miscellaneous drugs Amylin analogue :-Islet amyloid polypeptide, produced in beta cells -Acts in brain to reduce glucagon secretion, delay gastric emptying, retard glucose absorption, promote satiety Ex: pramlintide- synthetic, S.C injection before meal, used in Type 1 and 2 DM Bromocriptine: Quick release oral formulation used Adjunctive in T2 DM treatment Act on hypothalamic dopaminergic control of circardian rhythm of hormones (GH, Prolactin, ACTH) Used alone/ with metformin or SU or both

Oral hypoglycaemics mainly preferred in • Age above 40 at disease onset• Obesity at the time of presentation • Duration of disease < 5 years when starting treatment • FBS < 200mg/dl• Insulin requirement < 40 U/day• No ketoacidosis or history of it

Glucagon • Single chain polypeptide • Secreted by alpha cells • Secretion regulated by glucose levels, other nutrients, paracrine

hormones, nervous system • GLP-1, FFA, ketone bodies inhibit glucagon release • Enhance glycogenolysis and gluconeogenesis in liver • Increases the force and rate of cardiac contraction

Uses: 1.Hypoglycaemia – during emergency, not useful when hepatic glycogen is depleted Dose 0.5-1mg IV or IM2.Cardiogenic shock- not very marked action 3.To facilitate radiographic examination of upper/lower GIT tract by relaxing stomach and intestines

Other hyperglycaemics: Diazoxide, Somatostatin, Streptozocin

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